1. Field of the Invention
This invention relates to a method of preparing a compound having a pyridazino structure, namely ethyl{6-[ethyl-(2-hydroxypropyl)amino]-3-pyridazinyl}hydrazinocarboxylate. This compound exhibits a strong and lasting antihypertensive activity and causes retention of neither sodium nor liquids in the patients treated with it.
2. Summary of the Invention
The method according to this invention affords very high yields of ethyl{6-[ethyl-(2-hydroxypropyl)amino]-3-pyridazinyl}hydrazinocarboxylate through reactions which occur in extremely mild conditions, at room temperature and pressure.
In practice the starting material which comprises 3-chloro-6-hydrazinopyridazine is first protected at the hydrazino moiety, for example in the form of 3-chloro-6-(2-triphenylmethylhydrazino)pyridazine II, the reaction with the protecting halotriphenylmethane being carried out at 0.degree.-80.degree. C., preferably at room temperature in a suitable solvent like dichloromethane, or THF or chloroform. Then compound II is oxidized with an oxidizing agent selected from potassium permanganate, potassium dichromate or sodium hypochlorite in a suitable solvent like a halogenated hydrocarbon solvent such as dichloromethane or chloroform. Thus the reaction for example with potassium permanganate is carried out at a temperature of from 0.degree. to 40.degree. C., preferably at room temperature, by preferably operating in phase transfer, in the presence of catalytic amounts of a suitable catalyst such as a quanternary ammonium salt.
The corresponding azo derivative III thus formed is, in turn, treated with an aminoalcohol in the presence of a base such as potassium tert-butylate or sodium hydride which salifies the aminoalcohol reagent. This reaction with the aminoalcohol is carried out at 0.degree.-50.degree. C., preferably at room temperature in a suitable solvent.
The aminoderivative IV thus obtained is reduced to the compound of the formula V by hydrogenation with palladium on carbon, or with reducing agents such as sodium borohydride or sodium hydrosulphite at a temperature of from 0.degree. to 50.degree. C., preferably at room temperature in an alcohol or other suitable solvent.
Compound V is then deprotected by hydrolysis in the presence of mineral acids, in an alcoholic solvent, at 0.degree.-100.degree. C., preferably at room temperature, to yield the corresponding derivative VI, which is finally acylated with ethyl chlorocarbonate at a temperature of from -10.degree. C. to +20.degree. C., preferably 0.degree. C. in a suitable solvent, such as water, an alcohol, acetone, or their mixtures to obtain the desired compound.
This method may be summarized as follows: ##STR1##